We are studying the structure and function of malarial proteins inserted into the membrane of erythrocytes infected with mature asexual malaria parasites. Three malarial proteins have been identified at this site by our work to date. Two P. falciparum proteins are associated with knob protrusions of the erythrocyte membrane. Knobs mediate attachment of infected erythrocytes to endothelium, thereby preventing passage of infected cells through the spleen. A P. falciparum protein on the surface of the erythrocyte membrane has properties consistent with a role in cytoadherence: this protein displays exquisite trypsin sensitivity, as does cytoadherence to endothelium, and strain-specific sera which block or reverse cytoadherence of the homologous strain specifically immunoprecipitate this antigen from the homologous strain. This molecule exhibits size diversity between strains (Mr 260,000-290,000) in addition to antigenic diversity. The second erythrocyte membrane-associated P. falciparum protein is of unusually high histidine content (histidine-rich protein, HisRP). This protein is localized underneath the erythrocyte membrane at knobs Another HisRP of unknown function is soluble in neutral detergents, in contrast to the knob-associated HisRP. The Plasmodium knowlesi variant antigen on the surface of infected rhesus monkey erythrocytes is the third erythrocyte surface antigen. This parasite protein (Mr 180,000-230,000) varies antigenically in cloned organisms as a parasite immune evasion mechanism. Differential extraction experiments with detergents and protein show that this molecule is very tightly associated with the membrane, probably with both the lipid membrane and underlying cytoskeleton.